Project Summary/Abstract: Chronic pain is a prevalent disorder affecting approximately 100 million Americans. Treatment of chronic pain has heavily relied on opioid drugs, however; the use of opioids is accompanied with significant shortcomings including lack of efficacy in the long term and the risk for dependence that has contributed significantly to the national opioid epidemic. Thus, development and identification of novel strategies for pain management in chronic pain is a critical unmet need. A burgeoning body of literature suggests that the Cannabis plant has analgesic properties, with reported therapeutic effects ranging from substantial to conclusive in both preclinical and clinical studies. The main psychoactive constituent in the cannabis plant, tetrahydrocannabinol (THC) has demonstrated analgesic effects, however; its use is limited by adverse psychoactive and cognitive effects. However, not all isomers of THC demonstrate psychoactive effects. For example, cannabidiol (CBD) has been shown to demonstrate analgesic properties without psychoactive effects. The biological mechanisms underlying the analgesic efficacy of CBD are relatively unexplored and hence mechanistic studies investigating this research question are needed. CBD has a complex pharmacology with agonist and antagonist activity at several receptors including but not limited to endocannabinoid CB1 and CB2 receptors, serotonin 5-HT1A receptors, gamma-amino butyric acid receptors (GABA-A), and vanilloid receptors. In addition, CBD is a potent anti-inflammatory and has shown to decrease levels of cytokines and other pro-inflammatory signaling molecules. The goal of the proposed study, which responds to RFA-AT-19-009, is to evaluate changes in brain chemistry after a short-term (5-day) administration of a cannabis extract enriched in CBD using proton magnetic resonance spectroscopy (1H-MRS). 1H-MRS allows the measurement of in vivo levels of brain metabolites such as N-acetylaspartate, creatine, lactate, glutamate, GABA, glutamine (Gln), and myoinositol (mI). MRS studies of chronic pain have demonstrated changes in glutamate and GABA signaling in critical pain-processing regions of the brain. Furthermore, chronic pain has also been associated with increased levels of pro-inflammatory signaling molecules. Thus, pharmacological agents that can modulate central glutamate and GABAergic tone may exhibit potent analgesic activity. With the proposed study, we aim to investigate whether a short-term administration of a cannabis extract enriched in CBD can modulate glutamate and GABAergic signaling in critical pain-processing regions of the brain such as the anterior cingulate cortex (ACC) and insula. Furthermore, we plan to investigate the effects of CBD on peripheral and neural markers of inflammation. The successful completion of the study will advance the evidence-based application of CBD as a potential treatment for pain conditions and will also provide substrates that can be targeted to reduce neuroinflammation.